rs2302387

Variant names:

• chr7-87462869-G-A
• rs2302387
• NM_000443.4:c.175C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000443.4(ABCB4):​c.175C>T​(p.Leu59Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.159 in 1,612,594 control chromosomes in the GnomAD database, including 24,223 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (5350 hom., cov: 32)
  • Exomes 𝑓: 0.15 (18873 hom.)
• Consequence: ABCB4 NM_000443.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.790

Genes affected

ABCB4 (HGNC:45): (ATP binding cassette subfamily B member 4) The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MDR/TAP subfamily. Members of the MDR/TAP subfamily are involved in multidrug resistance as well as antigen presentation. This gene encodes a full transporter and member of the p-glycoprotein family of membrane proteins with phosphatidylcholine as its substrate. The function of this protein has not yet been determined; however, it may involve transport of phospholipids from liver hepatocytes into bile. Alternative splicing of this gene results in several products of undetermined function. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 7-87462869-G-A is Benign according to our data. Variant chr7-87462869-G-A is described in ClinVar as [Benign]. Clinvar id is 256158.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-87462869-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.79 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.437 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCB4	NM_000443.4	c.175C>T	p.Leu59Leu	synonymous_variant	Exon 4 of 28	ENST00000649586.2	NP_000434.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCB4	ENST00000649586.2	c.175C>T	p.Leu59Leu	synonymous_variant	Exon 4 of 28		NM_000443.4	ENSP00000496956.2

Frequencies

GnomAD3 genomes AF: 0.229 AC: 34844 AN: 151828 Hom.: 5330 Cov.: 32

Gnomad AFR AF: 0.442

Gnomad AMI AF: 0.126

Gnomad AMR AF: 0.160

Gnomad ASJ AF: 0.196

Gnomad EAS AF: 0.201

Gnomad SAS AF: 0.133

Gnomad FIN AF: 0.139

Gnomad MID AF: 0.180

Gnomad NFE AF: 0.143

Gnomad OTH AF: 0.198

GnomAD3 exomes AF: 0.170 AC: 42718 AN: 251194 Hom.: 4392 AF XY: 0.164 AC XY: 22247 AN XY: 135750

Gnomad AFR exome AF: 0.449

Gnomad AMR exome AF: 0.168

Gnomad ASJ exome AF: 0.188

Gnomad EAS exome AF: 0.194

Gnomad SAS exome AF: 0.141

Gnomad FIN exome AF: 0.139

Gnomad NFE exome AF: 0.140

Gnomad OTH exome AF: 0.165

GnomAD4 exome AF: 0.152 AC: 222260 AN: 1460648 Hom.: 18873 Cov.: 32 AF XY: 0.151 AC XY: 109789 AN XY: 726670

Gnomad4 AFR exome AF: 0.449

Gnomad4 AMR exome AF: 0.166

Gnomad4 ASJ exome AF: 0.188

Gnomad4 EAS exome AF: 0.223

Gnomad4 SAS exome AF: 0.140

Gnomad4 FIN exome AF: 0.139

Gnomad4 NFE exome AF: 0.140

Gnomad4 OTH exome AF: 0.170

GnomAD4 genome AF: 0.230 AC: 34914 AN: 151946 Hom.: 5350 Cov.: 32 AF XY: 0.226 AC XY: 16814 AN XY: 74264

Gnomad4 AFR AF: 0.442

Gnomad4 AMR AF: 0.160

Gnomad4 ASJ AF: 0.196

Gnomad4 EAS AF: 0.201

Gnomad4 SAS AF: 0.132

Gnomad4 FIN AF: 0.139

Gnomad4 NFE AF: 0.144

Gnomad4 OTH AF: 0.200

Alfa AF: 0.160 Hom.: 4779

Bravo AF: 0.241

Asia WGS AF: 0.188 AC: 655 AN: 3478

EpiCase AF: 0.144

EpiControl AF: 0.144

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 17, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cholestasis, intrahepatic, of pregnancy, 3 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Progressive familial intrahepatic cholestasis type 3 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	4.2
DANN	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2302387; hg19: chr7-87092185; COSMIC: COSV55942293;